The Branch has a long-standing involvement in the systematic evaluation of chemotherapeutic drugs alone or in combination with radiotherapy. As more individuals become long-term cancer survivors, there is greater need to evaluate risk-benefit ratios for various treatment protocols. Branch studies have shown that platinum-based chemotherapy for ovarian cancer was linked to a four-fold risk of leukemia; however, the substantial benefit that platinum-based treatment offers, outweighs the relatively small excess risk of leukemia. A study of leukemia following radiotherapy for testicular cancer revealed a three-fold elevated risk for leukemia, and this risk increased with increasing radiation dose to active bone marrow.The Branch is currently conducting an international cohort study of 32,000 Hodgkin's disease patients to evaluate the risk of radiation and chemotherapy induced second cancers. A study focussing on a subset of 6,000 children and adolescents with Hodgkin's disease indicated a high risk for second cancers of the thyroid and respiratory tract in patients treated before age ten; at older ages, the highest risks were seen for cancers of the digestive tract and breast. Bone marrow transplantation (BMT) has been an increasingly successful treatment for patients with high-risk leukemia, lymphoma and other malignant and non-malignant diseases. Evaluation of more than 20,000 BMT patients demonstrated an increased risk of Hodgkin's disease after BMT; an evaluation of more than 3,000 children undergoing BMT found over a 40-fold risk of new cancers. Follow-up for this study is being extended through 1996, with the goal of increasing the number of 5-year survivors of an allogeneic transplant from 3,300 to 6,000 and the number of 10-year survivors from 690 to 1,700.A cohort of 1,600 Retinoblastoma(RB) patients continues to be followed to monitor their cancer risk, and RB patients who have developed melanoma are undergoing clinical examination for dysplastic nevi syndrome, lipomas, and mutations in melanoma susceptibility genes. Recent Branch research has demonstrated that children treated for germ-line RB experience a markedly increased risk of lung cancer. Somatic mutations of the RB-1 gene are involved in the development of lung cancer. In collaboration with the Genetic Epidemiology Branch and cancer registries in four Nordic countries, breast cancer risk was reported to be increased in mothers, but not other female relatives, of patients with ataxia-telangiectasia. Sequencing of the ATM gene in patients and family members is also in progress.The Branch is currently estimating the risk of cancer after exposure to Thorotrast among several large populations. Thorotrast, once used as an angiographic contrast agent, is not excreted from the body to any appreciable extent; and has induced high rates of liver angiosarcoma and leukemia. The Branch recently completed a 40-year mortality follow-up of 693 Swedish patients with neurological disorders who received Thorotrast. A significant dose-response relation was found for all causes of death combined, and all malignant tumors combined.